Transgenic mice bearing specific altered cellular oncogenes represent a powerful new approach for testing the efficacy of these genes as tumorigenic agents, for determining how a single oncogene alters cell populations within the animal, for analysing how different oncogenes interact in diverse cell types, for exploring the pre-neoplastic state, and for creating a ready source of novel tumor cell lines. Recently we have shown that the c-myc oncogene, when driven by immunoglobulin u or k enhances Eu or Ek), elicits malignant lymphoma and lymphoblastic leukemia in transgenic mice. We propose to define the pathogenesis of this heritable disease, to assess the genetic influence of the host background, and to characterize the tumors in order to define the susceptible cell types and their capacity for self renewal and differentiation. The pre-neoplastic state we have identified in the young Eu-myc transgenic mice will be explored by analysis of the perturbations in lymphoid and other hematopoietic populations in vivo and the behavior of myc-driven cells in culture (e.g. factor dependence, persistence, proliferation rate). To assess oncogene cooperativity in hematopoietic cells, we will attempt to transform these pre- leukemic cells in vitro as well as searching for further oncogenic alterations within the tumor cells that arise spontaneously in vivo. The promising start with Eu-myc mice encourages us to make analogous mice bearing other oncogenes implicated in various lymphoid and other hemopoietic malignancies, including different versions of the myb, ras and abl genes. These studies should help to delineate how these oncogenes influence differentiation within the various hemopoietic lineages and provide valuable animal models for the early stages of leukemogenesis.